COMT inhibition as a potential therapeutic target among individuals with comorbid Alcohol Use Disorder and Attention-Deficit/Hyperactivity Disorder

COMT 抑制作为共病酒精使用障碍和注意力缺陷/多动障碍患者的潜在治疗靶点

• 批准号: 10369711
• 负责人: JOSEPH P. SCHACHT
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369711
• 关键词: Acceleration; Achievement; Adult; Advanced Development; Alcohol consumption; Alcohols; Alleles; Animal Model; Animals; Attention; Attention deficit hyperactivity disorder; Behavior; Brain; Brain Diseases; Catechol O-Methyltransferase; Child; Childhood; Clinical; Cognitive; Consumption; Corpus striatum structure; Crossover Design; Cues; Data; Decision Making; Disease; Dopamine; Dose; Double-Blind Method; Drug Prescriptions; Enrollment; Environment; Evaluation; FDA approved; Funding; General Population; Genotype; Homozygote; Human; Image; Impairment; Individual; Laboratories; Measures; Mediating; Methods; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Outcome; Parkinson Disease; Pharmaceutical Preparations; Pharmacogenetics; Placebo Control; Placebo Effect; Placebos; Population; Prefrontal Cortex; Process; Rewards; Self-control as a personality trait; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; Synapses; Testing; Time; alcohol comorbidity; alcohol cue; alcohol reward; alcohol use disorder; base; cognitive control; comorbidity; cue reactivity; design; dopamine transporter; drinking; heavy drinking young adult; improved; inhibitor; interest; neuroimaging; new therapeutic target; outcome prediction; placebo group; psychostimulant; recruit; selective attention; stimulant use; therapeutic target; tolcapone; Acceleration; Achievement; Adult; Advanced Development; Alcohol consumption; Alcohols; Alleles; Animal Model; Animals; Attention; Attention deficit hyperactivity disorder; Behavior; Brain; Brain Diseases; Catechol O-Methyltransferase; Child; Childhood; Clinical; Cognitive; Consumption; Corpus striatum structure; Crossover Design; Cues; Data; Decision Making; Disease; Dopamine; Dose; Double-Blind Method; Drug Prescriptions; Enrollment; Environment; Evaluation; FDA approved; Funding; General Population; Genotype; Homozygote; Human; Image; Impairment; Individual; Laboratories; Measures; Mediating; Methods; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Outcome; Parkinson Disease; Pharmaceutical Preparations; Pharmacogenetics; Placebo Control; Placebo Effect; Placebos; Population; Prefrontal Cortex; Process; Rewards; Self-control as a personality trait; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; Synapses; Testing; Time; alcohol comorbidity; alcohol cue; alcohol reward; alcohol use disorder; base; cognitive control; comorbidity; cue reactivity; design; dopamine transporter; drinking; heavy drinking young adult; improved; inhibitor; interest; neuroimaging; new therapeutic target; outcome prediction; placebo group; psychostimulant; recruit; selective attention; stimulant use; therapeutic target; tolcapone

ABSTRACT Alcohol Use Disorder (AUD) is a genetically influenced brain disease that is frequently comorbid with Attention- Deficit/Hyperactivity Disorder (ADHD), a neurodevelopmental disorder that arises in childhood and persists into adulthood in 30-45% of cases. The presence of one disorder significantly increases the likelihood of the other, and individuals with comorbid AUD/ADHD are a challenging clinical population. Both disorders are characterized by impairments in cognitive control, a process regulated in part by dopamine (DA) signaling in the prefrontal cortex (PFC). Psychostimulants, the most commonly prescribed medications for ADHD, elevate PFC DA tone and improve cognitive control. However, because psychostimulants also elevate striatal DA, they may potentiate alcohol’s rewarding and stimulating effects, and reduce its sedating effects, among individuals with comorbid AUD/ADHD. Non-stimulant medications have been tested in this population, but none has demonstrated effects on both AUD and ADHD symptoms. Tolcapone (TOLC), a brain-penetrant catechol-O-methyltransferase (COMT) inhibitor approved for the treatment of Parkinson’s disease, may more selectively potentiate cortical, but not striatal, DA release, and has shown promise in improving cognitive control and reducing drinking in animal models. TOLC’s effects may be influenced by a common single nucleotide polymorphism (SNP) in COMT that regulates COMT efficacy. Individuals who carry the val allele of the COMT val158met SNP, which has been associated with relatively higher COMT activity (and thus, lower PFC DA tone), may be more likely to benefit from TOLC treatment. Our preliminary data indicate that TOLC reduces drinking among non-treatment-seeking individuals with AUD, and does so to a greater extent among those with more ADHD symptoms and among COMT val-allele carriers. This project aims to evaluate TOLC as a pharmacogenetic probe for AUD/ADHD treatment, by testing its effects on neuroimaging and laboratory-based AUD/ADHD measures and on drinking in the natural environment. A group of unmedicated individuals with comorbid AUD/ADHD will be recruited, and a within-subjects, placebo- controlled, double-blind design will be used to test TOLC and placebo effects on three sets of outcomes: 1) brain activation associated with cognitive control, selective attention, and alcohol cue reactivity; 2) alcohol subjective effects and risky decision-making after consumption of a standard drink in the lab; and 3) drinking over six days in the natural environment. Additionally, an exploratory aim will evaluate whether COMT val158met genotype moderates TOLC effects on any of these outcomes. Achievement of these aims will potentially advance brain- penetrant COMT inhibitors as a new treatment option for individuals with comorbid AUD/ADHD.

抽象的 酒精使用障碍（AUD）是一种受遗传影响的脑部疾病，经常与关注 - 赤字/多动障碍（ADHD），这是一种在童年时期出现的神经发育障碍 在30-45％的病例中成年。一种疾病的存在显着增加了另一个疾病的可能性， 和合并AUD/ADHD的个人是临床人群的挑战。两种疾病都是特征的 通过认知控制的障碍，在前额叶中部分由多巴胺（DA）信号调节的过程 皮质（PFC）。精神刺激剂，最常见的多动症处方药，提升PFC DA音调 并改善认知控制。但是，由于心理刺激剂也提升了纹状体DA，因此它们可能潜在 在合并症的人中，酒精的有益和刺激效果，并减少其镇静作用 AUD/ADHD。在该人群中已经测试了非刺激药物，但没有一个表现出作用 在AUD和ADHD症状上。 tolcapone（TOLC），一种脑培养剂儿茶酚-O-甲基转移酶 （COMT）批准用于治疗帕金森氏病的抑制剂可能会更有选择性的皮质， 但不是纹状体，DA释放，并且在改善认知控制和减少动物饮酒方面表现出了希望 型号。 TOLC的效果可能受到COMT中常见的单核苷酸多态性（SNP）的影响 调节COMT效率。携带COMT Val158met SNP的Val等位基因的个人 与相对较高的COMT活性相关（因此，PFC DA音调较低）可能更有可能受益 来自TOLC治疗。我们的初步数据表明TOLC减少了非治疗寻求治疗的饮酒 具有AUD的人，并且在具有更多多动症症状的患者中更大程度地做到这一点 COMT Val-Allele载体。 该项目旨在通过测试其效果来评估TOLC作为AUD/ADHD处理的药物遗传学探针 关于神经影像学和基于实验室的AUD/ADHD测量以及在自然环境中饮酒。一个 将招募具有合并AUD/ADHD的未经物体的人群，并受试者内部，安慰剂 - 受控的双盲设计将用于测试三组结果的TOLC和安慰剂作用：1）大脑 与认知控制，选择性注意和酒精提示反应性相关的激活； 2）酒精主观 在实验室消费标准饮料后的影响和危险的决策； 3）在六天内喝酒 在自然环境中。此外，探索目的将评估COMT Val158met基因型是否 调节TOLC对这些结果中的任何一个。这些目标的实现将有可能提高大脑 - 渗透剂COMT抑制剂是合并AUD/ADHD的个体的新治疗选择。